DESCRIPTION: Genetics is the major component of cleft lip and palate susceptibility. Despite efforts to understand this condition, there is much more that needs to be learned. One line of investigation is to consider clefting as only a part of a broader phenotype. This proposal will focus on Dental development to sub-phenotype the common multifactor cleft lip and palate. We posit that tooth agenesis and/or other Dental anomalies could be clinical markers for the risk of having a child with isolated cleft lip and palate. We will focus on a population from the Philippines to take advantage of preliminary data collection already available. In this project, the Specific Aims include: 1) clinical characterization of multifactorial cleft lip and palate through cleft lip and palate case ascertainment along with complete Dental exam; 2) genetics studies of cleft lip and palate by a combination of candidate gene association/TDT and linkage approaches, and; 3) studies of gene-gene and gene-environment interactions. Complete Dental exams will be performed in 154 families from the Philippines with two or more affected siblings. Dental anomalies will be included as an extended phenotype of clefts. These Filipino families already possess substantial molecular information for a number of candidate genes and loci. Also, 392 STRP markers across the genome were typed on these families by The Center for Inherited Disease Research (CIDR) and a genome wide search for cleft loci was performed. Control families will be collected for a complementary case-control approach. We will compare the genetic analyses performed with and without Dental information to identify clefting sub-phenotypes. If our hypothesis is confirmed, we will be able to offer a very powerful tool for advancing etiologic studies of cleft lip and palate and will improve genetic counseling. Dental exams could be applied as screening tool for modifying population risks for cleft lip and palate.